The ethanolamides of long-chain fatty acids, or fatty acid ethanolamides (FAEs), are a class of bioactive lipids that serve important signaling function in both plants and animals (Piomelli, D. Trends Endocr Metab 2013; 24: 332-341). Polyunsaturated FAEs such as arachidonoylethanolamide (anandamide) are endogenous agonists (endocannabinoids) for type 1 and type 2 cannabinoid receptors, CB1 and CB2, and participate in the control of stress-coping responses and pain initiation (Calignano, A. et al., Nature 1998; 394: 277-281). On the other hand, monounsaturated and saturated FAEs, such as oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), regulate energy balance, pain and inflammation primarily by engaging peroxisome proliferator-activated receptor-α (PPAR-α), a member of the nuclear receptor superfamily (Fu, J. et al., Nature 2003; 425: 90-93; Schwartz, G. J. et al., Cell Metab 2008; 8(4): 281-288; LoVerme, J. et al., J Pharm Exp Ther 2006; 19(3):1051-1061).
Since the discovery that Δ9-tetrahydrocannabinol (THC), the primary bioactive constituent of the cannabis plant, interacts with CB1 and CB2 receptors, several synthetic cannabinoid receptor agonists have been prepared. Some CB1 agonists, deriving from chemical modification of THC, have been approved for the treatment of different pathological conditions, such as anorexia nervosa (Marinol), refractory chemotherapy-induced nausea and vomiting (Nabilone), neuropathic pain induced by multiple sclerosis, and adjunctive treatment of advanced cancer pain (Sativex).
The therapeutic potential of direct-acting cannabinoid agonists is limited by an undesirable profile of side effects, which includes dysphoria, dizziness, and effects on motor coordination and memory. An alternative strategy to achieve the desired modulation of cannabinoid receptor activity, without exposing patients to the risk of serious side effects, consists in increasing endocannabinoid levels (Cravatt, B. F., Lichtman, A. H. Curr Opin Chem Biol 2003; 7:469-475; Piomelli, D. Curr Opin Investig Drugs 2005; 6:672-679).
Endocannabinoids and other fatty acid ethanolamides are not stored in the cell, but are produced on demand, and their levels are regulated by enzymes responsible for their synthesis and degradation (Piomelli, D. Trends Endocr Metab 2013; 24: 332-341; Di Marzo, V., et al. Curr Opin Lipidol 2007; 18(2): 129-140; (Ueda, N., et al. Prog Lipid Res 2010; 49(4): 299-315). In particular, anandamide is inactivated via a two-step process consisting of high-affinity transport into cells (Di Marzo, V. et al. Nature 1994; 372: 686-691; Beltramo, M. et al. Science 1997; 277: 1094-1097) followed by intracellular degradation catalysed by fatty acid amide hydrolase (McKinney, M. K. and Cravatt, B. F. Annu Rev Biochem 2005; 74: 411-432), thus releasing arachidonic acid and ethanolamine.
Fatty acid amide hydrolase (FAAH) is a membrane-bound serine hydrolase that belongs to the amidase signature family of hydrolases. The active site of FAAH is characterized by an atypical catalytic triad consisting in Ser241-Ser217-Lys142, which is capable of hydrolysing amide and ester bonds at similar rates (Ahn, K., et al. Chem Rev 2008; 108(5): 1687-1707; McKinney, M. K., et al. Annual Rev Biochem 2005; 74: 411-432). FAAH can catalyse the hydrolysis of the amide bond of PEA and OEA (Muccioli, G. G. Drug Discovery Today 2010; 15(11-12): 474-483; Boger, D. L., et al. Curr Pharm Des 1998; 4(4): 303-314), and regulates the endogenous levels of other classes of amide-derived lipids, such as the N-acyl taurines (NATs), which activate transient receptor potential (TRP) (Saghatelian, A., et al. Biochemistry-U 2006; 45(30): 9007-9015) ions channels, and fatty acid primary amides (FAPAs) (Fowler, C. J., et al. Br J Pharmacol 2004; 141(2): 195-196), like the sleep-inducing lipid oleamide. A second isoform of FAAH, named FAAH-2 was isolated from the human ovarian cancer cell line OVCAR-3 and the breast cancer cell line MCF-7. This second isoform shares 20% homology with FAAH and shows a higher affinity for oleamide than anandamide (Wei, B. Q., et al. J Biol Chem 2006; 281(48): 36569-36578). FAAH-2 also differs from FAAH-1 for the intracellular localization, as it is found in the lipid droplets and not in the membrane of the endoplasmic reticulum.
Several disease conditions are characterized by alterations in the endogenous levels of the biomolecules hydrolysed by FAAH. Therefore, this enzyme has been considered a target for modulating endocannabinoid and other fatty acid ethanolamide levels in vivo (Hansen, H. S., et al. Exp Neurol 2010; 224(1): 48-55). Substantial efforts have been directed to the discovery of potent and selective FAAH inhibitors, aiming at the development of new therapeutic approaches for the treatment of several pathologic conditions, including pain, inflammation, appetite regulation, anxiety, and depression (Piomelli, D. Curr Opin Investig Drugs 2005; 6: 672-679; Lambert, D. M., et al. Curr Opin Clin Nutr Metab Care 2007; 10(6): 735-744; Di Marzo, V. et al. Nat Rev Drug Discov 2008; 7(5): 438-455).
FAAH inhibitors having improved adsorption and/or oral bioavailability (F %) are of particular therapeutic interest in order to decrease the daily dose administered while maintaining therapeutic afficacy and improving patient's compliance. Provided herein, inter alia, are solutions to these and other problems in the art.